Abstract：
L-type voltage-gated calcium channels (L-VGCCs) are thought to be involved in epileptogenesis and acute excitotoxicity. However, little is known about the role of L-VGCCs in neuroinflammation or delayed neuronal death following excitotoxic insult. We examined the effects of repeated treatment with the L-VGCC blocker nimodipine on neuroinflammatory changes and delayed neuronal apoptosis in the dentate gyrus following trimethyltin (TMT)-induced convulsions. Male C57BL/6 N mice were administered TMT (2.6 mg/kg, i.p.), and the expression of the Cav1.2 and Cav1.3 subunits of L-VGCC were evaluated. The expression of both subunits was significantly decreased; however, the astroglial expression of Cav1.3 L-VGCC was significantly induced at 6 and 10 days after TMT treatment. Furthermore, astroglial Cav1.3 L-VGCCs colocalized with both the pro-inflammatory phenotype marker C3 and the anti-inflammatory phenotype marker S100A10 of astrocytes. Nimodipine (5 mg/kg, i.p. × 5 at 12-h intervals) did not significantly affect TMT-induced astroglial activation. However, nimodipine significantly attenuated the pro-inflammatory phenotype changes, while enhancing the anti-inflammatory phenotype changes in astrocytes after TMT treatment. Consistently, nimodipine reduced the levels of pro-inflammatory astrocytes-to-microglia mediators, while increasing the levels of anti-inflammatory astrocytes-to-microglia mediators. These effects were accompanied by an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), supporting our previous finding that p-ERK is a signaling factor that regulates astroglial phenotype changes. In addition, nimodipine significantly attenuated TMT-induced microglial activation and delayed apoptosis of dentate granule neurons. Our results suggest that L-VGCC blockade attenuates neuroinflammation and delayed neurotoxicity following TMT-induced convulsions through the regulation of astroglial phenotypic changes by promoting ERK signaling.
摘要：
L型电压门控钙通道（L-VGCC）被认为与癫痫发生和急性兴奋性毒性有关。然而,关于L-VGCC在兴奋性毒性损伤后的神经炎症或迟发性神经元死亡中的作用知之甚少。我们研究了用L-VGCC阻滞剂尼莫地平反复治疗对三甲基锡（TMT）引起的惊厥后齿状回的神经炎性变化和神经元凋亡延迟的影响。雄性C57BL/6N小鼠给予TMT(2.6mg/kg，i.p.),并评估了L-VGCC的Cav1.2和Cav1.3亚基的表达。两个亚基的表达均显着降低；然而，在TMT治疗后第6天和第10天，Cav1.3L-VGCC的星形胶质细胞表达被显著诱导。此外，星形胶质细胞Cav1.3L-VGCC与星形胶质细胞的促炎表型标记C3和抗炎表型标记S100A10共同定位。尼莫地平（5mg/kg，i.p.间隔12小时×5）不会显着影响TMT诱导的星形胶质细胞活化。然而,尼莫地平可显着减轻促炎表型的变化，同时增强TMT治疗后星形胶质细胞的抗炎表型变化。始终如一，尼莫地平降低了促炎星形胶质细胞到小胶质细胞介质的水平，同时增加抗炎星形胶质细胞到小胶质细胞介质的水平。这些作用伴随着细胞外信号调节激酶（ERK）磷酸化的增加，支持我们之前的发现，即p-ERK是调节星形胶质细胞表型变化的信号因子。此外,尼莫地平可显着减弱TMT诱导的小胶质细胞活化和齿状颗粒神经元的延迟凋亡。我们的结果表明，L-VGCC阻断通过促进ERK信号传导来调节星形胶质细胞表型变化，从而减轻TMT引起的惊厥后的神经炎症和延迟性神经毒性。
